Abstract 17: Ultra-early Activation Of Neuroinflammatory Cascade Following Acute Stroke: Plasma And Extracellular Vesicle Biomarkers From A Mobile Stroke Unit

Background: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We used a mobile stroke unit (MSU) to identify the onset of the neuroinflammatory cascade within minutes of symptom onset. Methods: The study is a prospective, cohort investigation of ultra-early blood- and extracellular vesicle (EV)-derived markers of neuroinflammation and outcome in acute stroke. Blood was obtained on the MSU with head CT, and from healthy controls. Plasma biomarkers were analyzed with ELISA, SIMOA and ECL. EVs were isolated with HSP pull down. Confirmed strokes, mimics and healthy controls were compared. Variables included demographics, mRS, NIHSS and discharge disposition. Results: Forty one adults were analyzed, including 15 patients treated on the MSU between August 2021 and April 2022, and 26 controls. For MSU patients, median age was 74 (range 36-97) years, 60% were female, and 80% white. Ten (67%) were diagnosed as stroke, with 8 (53%) confirmed and 2 likely TIA or stroke averted by thrombolysis; 5 were stroke mimics. For strokes, median initial NIHSS score was 11 (range 4-19) and 6 (75%) received tPA. Blood was obtained a median of 58 (range 36-133) minutes after symptom onset. Within 36 minutes after stroke, plasma interleukin-6 (IL-6), neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were elevated by as much as 10 times normal. In EVs, matrix metalloproteinase-9 (MMP-9), chemokine (C-X-C motif) ligand 4 (CXCL4), C-reactive protein (CRP), IL-6, osteopontin (OPN) and platelet and endothelial cell adhesion molecule 1 (PECAM1) were elevated. Inflammatory markers increased rapidly in the first two hours, and continued rising for 24 hours. Conclusions: This study found the inflammatory cascade is activated as early as 36 minutes after stroke, and progresses rapidly. This is earlier than observed previously in humans, and suggests injury from neuroinflammation may occur faster than had been surmised. The findings may inform development of immunomodulatory therapies for acute stroke, and lead to new diagnostic tools and improved outcomes.